1932

Abstract

Macrophages are a diverse set of cells present in all body compartments. This diversity is imprinted by their ontogenetic origin (embryonal versus adult bone marrow–derived cells); the organ context; by their activation or deactivation by various signals in the contexts of microbial invasion, tissue damage, and metabolic derangement; and by polarization of adaptive T cell responses. Classic adaptive responses of macrophages include tolerance, priming, and a wide spectrum of activation states, including M1, M2, or M2-like. Moreover, macrophages can retain long-term imprinting of microbial encounters (trained innate immunity). Single-cell analysis of mononuclear phagocytes in health and disease has added a new dimension to our understanding of the diversity of macrophage differentiation and activation. Epigenetic landscapes, transcription factors, and microRNA networks underlie the adaptability of macrophages to different environmental cues. Macrophage plasticity, an essential component of chronic inflammation, and its involvement in diverse human diseases, most notably cancer, is discussed here as a paradigm.

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2020-01-24
2024-06-17
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Literature Cited

  1. 1. 
    Gordon S, Taylor PR. 2005. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5:953–64
    [Google Scholar]
  2. 2. 
    Ginhoux F, Guilliams M. 2016. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44:439–49
    [Google Scholar]
  3. 3. 
    Pollard JW. 2009. Trophic macrophages in development and disease. Nat. Rev. Immunol. 9:259–70
    [Google Scholar]
  4. 4. 
    Link VM, Duttke SH, Chun HB, Holtman IR, Westin E et al. 2018. Analysis of genetically diverse macrophages reveals local and domain-wide mechanisms that control transcription factor binding and function. Cell 173:1796–809.e17
    [Google Scholar]
  5. 5. 
    Molgora M, Supino D, Mavilio D, Santoni A, Moretta L et al. 2018. The yin–yang of the interaction between myelomonocytic cells and NK cells. Scand. J. Immunol. 88:e12705
    [Google Scholar]
  6. 6. 
    Garlanda C, Bottazzi B, Bastone A, Mantovani A 2005. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu. Rev. Immunol. 23:337–66
    [Google Scholar]
  7. 7. 
    Netea MG, Balkwill F, Chonchol M, Cominelli F, Donath MY et al. 2017. A guiding map for inflammation. Nat. Immunol. 18:826–31
    [Google Scholar]
  8. 8. 
    Mantovani A, Dinarello CA, Molgora M, Garlanda C 2019. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50:778–95
    [Google Scholar]
  9. 9. 
    Biswas SK, Lopez-Collazo E. 2009. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 30:475–87
    [Google Scholar]
  10. 10. 
    Sica A, Mantovani A. 2012. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Investig. 122:787–95
    [Google Scholar]
  11. 11. 
    Mantovani A. 2016. Reflections on immunological nomenclature: in praise of imperfection. Nat. Immunol. 17:215–16
    [Google Scholar]
  12. 12. 
    Van Furth R 1980. Mononuclear Phagocytes: Functional Aspects The Hague: Springer
    [Google Scholar]
  13. 13. 
    Ginhoux F, Merad M. 2010. Ontogeny and homeostasis of Langerhans cells. Immunol. Cell Biol. 88:387–92
    [Google Scholar]
  14. 14. 
    Sawai CM, Babovic S, Upadhaya S, Knapp D, Lavin Y et al. 2016. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity 45:597–609
    [Google Scholar]
  15. 15. 
    Bajpai G, Schneider C, Wong N, Bredemeyer A, Hulsmans M et al. 2018. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 24:1234–45
    [Google Scholar]
  16. 16. 
    Bassler K, Schulte-Schrepping J, Warnat-Herresthal S, Aschenbrenner AC, Schultze JL 2019. The myeloid cell compartment—cell by cell. Annu. Rev. Immunol. 37:269–93
    [Google Scholar]
  17. 17. 
    Jordao MJC, Sankowski R, Brendecke SM, Sagar, Locatelli G et al. 2019. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363:eaat7554
    [Google Scholar]
  18. 18. 
    Li Q, Barres BA. 2018. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18:225–42
    [Google Scholar]
  19. 19. 
    Lapenna A, De Palma M, Lewis CE 2018. Perivascular macrophages in health and disease. Nat. Rev. Immunol. 18:689–702
    [Google Scholar]
  20. 20. 
    Frodermann V, Nahrendorf M. 2018. Macrophages and cardiovascular health. Physiol. Rev. 98:2523–69
    [Google Scholar]
  21. 21. 
    Hong C, Tontonoz P. 2014. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat. Rev. Drug Discov. 13:433–44
    [Google Scholar]
  22. 22. 
    Biswas SK, Mantovani A. 2012. Orchestration of metabolism by macrophages. Cell Metab 15:432–37
    [Google Scholar]
  23. 23. 
    Mackaness GB. 1969. The influence of immunologically committed lymphoid cells on macrophage activity in vivo. J. Exp. Med. 129:973–92
    [Google Scholar]
  24. 24. 
    Evans R, Alexander P. 1970. Cooperation of immune lymphoid cells with macrophages in tumour immunity. Nature 228:620–22
    [Google Scholar]
  25. 25. 
    Biswas SK, Mantovani A. 2010. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11:889–96
    [Google Scholar]
  26. 26. 
    Medzhitov R, Schneider DS, Soares MP 2012. Disease tolerance as a defense strategy. Science 335:936–41
    [Google Scholar]
  27. 27. 
    Schulthess J, Pandey S, Capitani M, Rue-Albrecht KC, Arnold I et al. 2019. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50:432–45.e7
    [Google Scholar]
  28. 28. 
    Bowdish DM, Loffredo MS, Mukhopadhyay S, Mantovani A, Gordon S 2007. Macrophage receptors implicated in the “adaptive” form of innate immunity. Microbes Infect 9:1680–87
    [Google Scholar]
  29. 29. 
    Garlanda C, Bottazzi B, Magrini E, Inforzato A, Mantovani A 2018. PTX3, a humoral pattern recognition molecule, in innate immunity, tissue repair, and cancer. Physiol. Rev. 98:623–39
    [Google Scholar]
  30. 30. 
    Stein M, Keshav S, Harris N, Gordon S 1992. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176:287–92
    [Google Scholar]
  31. 31. 
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–55
    [Google Scholar]
  32. 32. 
    Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P 2017. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14:399–416
    [Google Scholar]
  33. 33. 
    Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W et al. 2014. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40:274–88
    [Google Scholar]
  34. 34. 
    Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A et al. 2006. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation). Blood 107:2112–22
    [Google Scholar]
  35. 35. 
    Netea MG, Joosten LA, Latz E, Mills KH, Natoli G et al. 2016. Trained immunity: a program of innate immune memory in health and disease. Science 352:aaf1098
    [Google Scholar]
  36. 36. 
    Kurtz J, Franz K. 2003. Innate defence: evidence for memory in invertebrate immunity. Nature 425:37–38
    [Google Scholar]
  37. 37. 
    Bowdish DM, Loffredo MS, Mukhopadhyay S, Mantovani A, Gordon S 2007. Macrophage receptors implicated in the “adaptive” form of innate immunity. Microbes Infect 9:1680–87
    [Google Scholar]
  38. 38. 
    Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M et al. 2018. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172:147–61.e12
    [Google Scholar]
  39. 39. 
    Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M et al. 2018. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175:1634–50.e17
    [Google Scholar]
  40. 40. 
    Molawi K, Sieweke MH. 2013. Transcriptional control of macrophage identity, self-renewal, and function. Adv. Immunol. 120:269–300
    [Google Scholar]
  41. 41. 
    Natoli G. 2010. Maintaining cell identity through global control of genomic organization. Immunity 33:12–24
    [Google Scholar]
  42. 42. 
    Natoli G, Ghisletti S, Barozzi I 2011. The genomic landscapes of inflammation. Genes Dev 25:101–6
    [Google Scholar]
  43. 43. 
    Segal E, Fondufe-Mittendorf Y, Chen L, Thastrom A, Field Y et al. 2006. A genomic code for nucleosome positioning. Nature 442:772–78
    [Google Scholar]
  44. 44. 
    Struhl K, Segal E. 2013. Determinants of nucleosome positioning. Nat. Struct. Mol. Biol. 20:267–73
    [Google Scholar]
  45. 45. 
    Jiang C, Pugh BF. 2009. Nucleosome positioning and gene regulation: advances through genomics. Nat. Rev. Genet. 10:161–72
    [Google Scholar]
  46. 46. 
    Ghisletti S, Barozzi I, Mietton F, Polletti S, De Santa F et al. 2010. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32:317–28
    [Google Scholar]
  47. 47. 
    Ivashkiv LB. 2013. Epigenetic regulation of macrophage polarization and function. Trends Immunol 34:216–23
    [Google Scholar]
  48. 48. 
    Smale ST, Tarakhovsky A, Natoli G 2014. Chromatin contributions to the regulation of innate immunity. Annu. Rev. Immunol. 32:489–511
    [Google Scholar]
  49. 49. 
    Saccani S, Pantano S, Natoli G 2001. Two waves of nuclear factor κB recruitment to target promoters. J. Exp. Med. 193:1351–59
    [Google Scholar]
  50. 50. 
    Ramirez-Carrozzi VR, Nazarian AA, Li CC, Gore SL, Sridharan R et al. 2006. Selective and antagonistic functions of SWI/SNF and Mi-2β nucleosome remodeling complexes during an inflammatory response. Genes Dev 20:282–96
    [Google Scholar]
  51. 51. 
    Foster SL, Hargreaves DC, Medzhitov R 2007. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447:972–78
    [Google Scholar]
  52. 52. 
    Brown JD, Lin CY, Duan Q, Griffin G, Federation A et al. 2014. NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol. Cell 56:219–31
    [Google Scholar]
  53. 53. 
    Qiao Y, Giannopoulou EG, Chan CH, Park SH, Gong S et al. 2013. Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and Toll-like receptor signaling. Immunity 39:454–69
    [Google Scholar]
  54. 54. 
    Ishii M, Wen H, Corsa CA, Liu T, Coelho AL et al. 2009. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 114:3244–54
    [Google Scholar]
  55. 55. 
    Ostuni R, Natoli G. 2011. Transcriptional control of macrophage diversity and specialization. Eur. J. Immunol. 41:2486–90
    [Google Scholar]
  56. 56. 
    Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A et al. 2013. Latent enhancers activated by stimulation in differentiated cells. Cell 152:157–71
    [Google Scholar]
  57. 57. 
    Kang K, Park SH, Chen J, Qiao Y, Giannopoulou E et al. 2017. Interferon-γ represses M2 gene expression in human macrophages by disassembling enhancers bound by the transcription factor MAF. Immunity 47:235–50.e4
    [Google Scholar]
  58. 58. 
    Shalova IN, Lim JY, Chittezhath M, Zinkernagel AS, Beasley F et al. 2015. Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1α. Immunity 42:484–98
    [Google Scholar]
  59. 59. 
    Yan Q, Carmody RJ, Qu Z, Ruan Q, Jager J et al. 2012. Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome. PNAS 109:14140–45
    [Google Scholar]
  60. 60. 
    Novakovic B, Habibi E, Wang SY, Arts RJW, Davar R et al. 2016. β-glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167:1354–68.e14
    [Google Scholar]
  61. 61. 
    Chen J, Ivashkiv LB. 2010. IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. PNAS 107:19438–43
    [Google Scholar]
  62. 62. 
    Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A et al. 2014. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345:1251086
    [Google Scholar]
  63. 63. 
    Benit P, Letouze E, Rak M, Aubry L, Burnichon N et al. 2014. Unsuspected task for an old team: succinate, fumarate and other Krebs cycle acids in metabolic remodeling. Biochim. Biophys. Acta Bioenerg. 1837:1330–37
    [Google Scholar]
  64. 64. 
    Squadrito ML, Etzrodt M, De Palma M, Pittet MJ 2013. MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol 34:350–59
    [Google Scholar]
  65. 65. 
    Liu G, Abraham E. 2013. MicroRNAs in immune response and macrophage polarization. Arterioscler. Thromb. Vasc. Biol. 33:170–77
    [Google Scholar]
  66. 66. 
    Guo S, Lu J, Schlanger R, Zhang H, Wang JY et al. 2010. MicroRNA miR-125a controls hematopoietic stem cell number. PNAS 107:14229–34
    [Google Scholar]
  67. 67. 
    Zhong Y, Yi C. 2016. MicroRNA-720 suppresses M2 macrophage polarization by targeting GATA3. Biosci. Rep. 36:e00363
    [Google Scholar]
  68. 68. 
    Ying H, Kang Y, Zhang H, Zhao D, Xia J et al. 2015. MiR-127 modulates macrophage polarization and promotes lung inflammation and injury by activating the JNK pathway. J. Immunol. 194:1239–51
    [Google Scholar]
  69. 69. 
    Nazari-Jahantigh M, Wei Y, Noels H, Akhtar S, Zhou Z et al. 2012. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J. Clin. Investig. 122:4190–202
    [Google Scholar]
  70. 70. 
    Cai X, Yin Y, Li N, Zhu D, Zhang J et al. 2012. Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. J. Mol. Cell Biol. 4:341–43
    [Google Scholar]
  71. 71. 
    Jablonski KA, Gaudet AD, Amici SA, Popovich PG, Guerau-de-Arellano M 2016. Control of the inflammatory macrophage transcriptional signature by miR-155. PLOS ONE 11:e0159724
    [Google Scholar]
  72. 72. 
    Martinez-Nunez RT, Louafi F, Sanchez-Elsner T 2011. The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor α1 (IL13Rα1). J. Biol. Chem. 286:1786–94
    [Google Scholar]
  73. 73. 
    Zhang Y, Zhang M, Li X, Tang Z, Wang X et al. 2016. Silencing microRNA-155 attenuates cardiac injury and dysfunction in viral myocarditis via promotion of M2 phenotype polarization of macrophages. Sci. Rep. 6:22613
    [Google Scholar]
  74. 74. 
    Li D, Duan M, Feng Y, Geng L, Li X, Zhang W 2016. MiR-146a modulates macrophage polarization in systemic juvenile idiopathic arthritis by targeting INHBA. Mol. Immunol. 77:205–12
    [Google Scholar]
  75. 75. 
    Huang C, Liu XJ, QunZhou Xie J, Ma TT et al. 2016. MiR-146a modulates macrophage polarization by inhibiting Notch1 pathway in RAW264.7 macrophages. Int. Immunopharmacol. 32:46–54
    [Google Scholar]
  76. 76. 
    Zhou H, Xiao J, Wu N, Liu C, Xu J et al. 2015. MicroRNA-223 regulates the differentiation and function of intestinal dendritic cells and macrophages by targeting C/EBPβ. Cell Rep 13:1149–60
    [Google Scholar]
  77. 77. 
    Ying W, Tseng A, Chang RC, Morin A, Brehm T et al. 2015. MicroRNA-223 is a crucial mediator of PPARγ-regulated alternative macrophage activation. J. Clin. Investig. 125:4149–59
    [Google Scholar]
  78. 78. 
    Zhang W, Liu H, Liu W, Liu Y, Xu J 2015. Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway. Cell Death Differ 22:287–97
    [Google Scholar]
  79. 79. 
    Banerjee S, Xie N, Cui H, Tan Z, Yang S et al. 2013. MicroRNA let-7c regulates macrophage polarization. J. Immunol. 190:6542–49
    [Google Scholar]
  80. 80. 
    Ruckerl D, Jenkins SJ, Laqtom NN, Gallagher IJ, Sutherland TE et al. 2012. Induction of IL-4Rα-dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4-driven murine macrophage proliferation in vivo. Blood 120:2307–16
    [Google Scholar]
  81. 81. 
    Squadrito ML, Pucci F, Magri L, Moi D, Gilfillan GD et al. 2012. miR-511–3p modulates genetic programs of tumor-associated macrophages. Cell Rep 1:141–54
    [Google Scholar]
  82. 82. 
    Ma S, Liu M, Xu Z, Li Y, Guo H et al. 2016. A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1 versus M2 macrophage polarization and thus regulates cancer progression. Oncotarget 7:13502–19
    [Google Scholar]
  83. 83. 
    Mathsyaraja H, Thies K, Taffany DA, Deighan C, Liu T et al. 2015. CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. Oncogene 34:3651–61
    [Google Scholar]
  84. 84. 
    Wang Z, Brandt S, Medeiros A, Wang S, Wu H et al. 2015. MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation. PLOS ONE 10:e0115855
    [Google Scholar]
  85. 85. 
    Curtale G, Mirolo M, Renzi TA, Rossato M, Bazzoni F, Locati M 2013. Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b. PNAS 110:11499–504
    [Google Scholar]
  86. 86. 
    O'Neill LA, Sheedy FJ, McCoy CE 2011. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat. Rev. Immunol. 11:163–75
    [Google Scholar]
  87. 87. 
    Deng H, Maitra U, Morris M, Li L 2013. Molecular mechanism responsible for the priming of macrophage activation. J. Biol. Chem. 288:3897–906
    [Google Scholar]
  88. 88. 
    Taganov KD, Boldin MP, Chang KJ, Baltimore D 2006. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. PNAS 103:12481–86
    [Google Scholar]
  89. 89. 
    O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D 2007. MicroRNA-155 is induced during the macrophage inflammatory response. PNAS 104:1604–9
    [Google Scholar]
  90. 90. 
    El Gazzar M, McCall CE 2010. MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. J. Biol. Chem. 285:20940–51
    [Google Scholar]
  91. 91. 
    El Gazzar M, Church A, Liu T, McCall CE 2011. MicroRNA-146a regulates both transcription silencing and translation disruption of TNF-α during TLR4-induced gene reprogramming. J. Leukoc. Biol. 90:509–19
    [Google Scholar]
  92. 92. 
    Doxaki C, Kampranis SC, Eliopoulos AG, Spilianakis C, Tsatsanis C 2015. Coordinated regulation of miR-155 and miR-146a genes during induction of endotoxin tolerance in macrophages. J. Immunol. 195:5750–61
    [Google Scholar]
  93. 93. 
    Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S et al. 2009. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31:220–31
    [Google Scholar]
  94. 94. 
    Wang P, Hou J, Lin L, Wang C, Liu X et al. 2010. Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J. Immunol. 185:6226–33
    [Google Scholar]
  95. 95. 
    O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D 2009. Inositol phosphatase SHIP1 is a primary target of miR-155. PNAS 106:7113–18
    [Google Scholar]
  96. 96. 
    Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O'Leary JJ et al. 2010. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat. Immunol. 11:141–47
    [Google Scholar]
  97. 97. 
    McCoy CE, Sheedy FJ, Qualls JE, Doyle SL, Quinn SR et al. 2010. IL-10 inhibits miR-155 induction by Toll-like receptors. J. Biol. Chem. 285:20492–98
    [Google Scholar]
  98. 98. 
    Curtale G, Renzi TA, Mirolo M, Drufuca L, Albanese M et al. 2018. Multi-step regulation of the TLR4 pathway by the miR-125a∼99b∼let-7e cluster. Front. Immunol. 9:2037
    [Google Scholar]
  99. 99. 
    Chaudhuri AA, So AY, Sinha N, Gibson WS, Taganov KD et al. 2011. MicroRNA-125b potentiates macrophage activation. J. Immunol. 187:5062–68
    [Google Scholar]
  100. 100. 
    Renzi TA, Rubino M, Gornati L, Garlanda C, Locati M, Curtale G 2015. MiR-146b mediates endotoxin tolerance in human phagocytes. Mediat. Inflamm. 2015:145305
    [Google Scholar]
  101. 101. 
    Curtale G, Renzi TA, Drufuca L, Rubino M, Locati M 2017. Glucocorticoids downregulate TLR4 signaling activity via its direct targeting by miR-511-5p. Eur. J. Immunol. 47:2080–89
    [Google Scholar]
  102. 102. 
    Minutti CM, Jackson-Jones LH, Garcia-Fojeda B, Knipper JA, Sutherland TE et al. 2017. Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver. Science 356:1076–80
    [Google Scholar]
  103. 103. 
    Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD et al. 2017. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 356:1072–76
    [Google Scholar]
  104. 104. 
    Tabas I, Lichtman AH. 2017. Monocyte-macrophages and T cells in atherosclerosis. Immunity 47:621–34
    [Google Scholar]
  105. 105. 
    Hansson GK. 2005. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352:1685–95
    [Google Scholar]
  106. 106. 
    Udalova IA, Mantovani A, Feldmann M 2016. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat. Rev. Rheumatol. 12:472–85
    [Google Scholar]
  107. 107. 
    Coussens LM, Zitvogel L, Palucka AK 2013. Neutralizing tumor-promoting chronic inflammation: a magic bullet?. Science 339:286–91
    [Google Scholar]
  108. 108. 
    De Palma M, Biziato D, Petrova TV 2017. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17:457–74
    [Google Scholar]
  109. 109. 
    Qian BZ, Pollard JW. 2010. Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51
    [Google Scholar]
  110. 110. 
    Bolli E, Movahedi K, Laoui D, Van Ginderachter JA 2017. Novel insights in the regulation and function of macrophages in the tumor microenvironment. Curr. Opin. Oncol. 29:55–61
    [Google Scholar]
  111. 111. 
    Murray PJ. 2018. Immune regulation by monocytes. Semin. Immunol. 35:12–18
    [Google Scholar]
  112. 112. 
    Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L 1992. The origin and function of tumor-associated macrophages. Immunol. Today 13:265–70
    [Google Scholar]
  113. 113. 
    Zhu Y, Herndon JM, Sojka DK, Kim KW, Knolhoff BL et al. 2017. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47:323–38.e6
    [Google Scholar]
  114. 114. 
    Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR et al. 2014. The cellular and molecular origin of tumor-associated macrophages. Science 344:921–25
    [Google Scholar]
  115. 115. 
    Hambardzumyan D, Gutmann DH, Kettenmann H 2016. The role of microglia and macrophages in glioma maintenance and progression. Nat. Neurosci. 19:20–27
    [Google Scholar]
  116. 116. 
    Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM et al. 2017. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J. Exp. Med. 214:2387–404
    [Google Scholar]
  117. 117. 
    Lee SH, Charmoy M, Romano A, Paun A, Chaves MM et al. 2018. Mannose receptor high, M2 dermal macrophages mediate nonhealing Leishmania major infection in a Th1 immune environment. J. Exp. Med. 215:357–75
    [Google Scholar]
  118. 118. 
    Liou GY, Bastea L, Fleming A, Doppler H, Edenfield BH et al. 2017. The presence of interleukin-13 at pancreatic ADM/PanIN lesions alters macrophage populations and mediates pancreatic tumorigenesis. Cell Rep 19:1322–33
    [Google Scholar]
  119. 119. 
    Afik R, Zigmond E, Vugman M, Klepfish M, Shimshoni E et al. 2016. Tumor macrophages are pivotal constructors of tumor collagenous matrix. J. Exp. Med. 213:2315–31
    [Google Scholar]
  120. 120. 
    Guo X, Zhao Y, Yan H, Yang Y, Shen S et al. 2017. Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev 31:247–59
    [Google Scholar]
  121. 121. 
    Canli O, Nicolas AM, Gupta J, Finkelmeier F, Goncharova O et al. 2017. Myeloid cell-derived reactive oxygen species induce epithelial mutagenesis. Cancer Cell 32:869–83.e5
    [Google Scholar]
  122. 122. 
    Doak GR, Schwertfeger KL, Wood DK 2018. Distant relations: macrophage functions in the metastatic niche. Trends Cancer 4:445–59
    [Google Scholar]
  123. 123. 
    Wei J, Marisetty A, Schrand B, Gabrusiewicz K, Hashimoto Y et al. 2019. Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. J. Clin. Investig. 129:137–49
    [Google Scholar]
  124. 124. 
    Ubil E, Caskey L, Holtzhausen A, Hunter D, Story C, Earp HS 2018. Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. J. Clin. Investig. 128:2356–69
    [Google Scholar]
  125. 125. 
    Lan J, Sun L, Xu F, Liu L, Hu F et al. 2019. M2 macrophage-derived exosomes promote cell migration and invasion in colon cancer. Cancer Res 79:146–58
    [Google Scholar]
  126. 126. 
    Saha S, Shalova IN, Biswas SK 2017. Metabolic regulation of macrophage phenotype and function. Immunol. Rev. 280:102–11
    [Google Scholar]
  127. 127. 
    Weiss JM, Davies LC, Karwan M, Ileva L, Ozaki MK et al. 2018. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J. Clin. Investig. 128:3794–805
    [Google Scholar]
  128. 128. 
    Bohn T, Rapp S, Luther N, Klein M, Bruehl TJ et al. 2018. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat. Immunol. 19:1319–29
    [Google Scholar]
  129. 129. 
    Alaeddine M, Prat M, Poinsot V, Gouaze-Andersson V, Authier H et al. 2019. IL13-mediated dectin-1 and mannose receptor overexpression promotes macrophage antitumor activities through recognition of sialylated tumor cells. Cancer Immunol. Res. 7:321–34
    [Google Scholar]
  130. 130. 
    Mattiola I, Tomay F, De Pizzol M, Silva-Gomes R, Savino B et al. 2019. The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell–mediated resistance to metastasis. Nat. Immunol. 20:1012–22
    [Google Scholar]
  131. 131. 
    Reis ES, Mastellos DC, Ricklin D, Mantovani A, Lambris JD 2018. Complement in cancer: untangling an intricate relationship. Nat. Rev. Immunol. 18:5–18
    [Google Scholar]
  132. 132. 
    Bonavita E, Gentile S, Rubino M, Maina V, Papait R et al. 2015. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160:700–14
    [Google Scholar]
  133. 133. 
    Rubino M, Kunderfranco P, Basso G, Greco CM, Pasqualini F et al. 2017. Epigenetic regulation of the extrinsic oncosuppressor PTX3 gene in inflammation and cancer. OncoImmunology 6:e1333215
    [Google Scholar]
  134. 134. 
    Medler TR, Murugan D, Horton W, Kumar S, Cotechini T et al. 2018. Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell 34:561–78.e6
    [Google Scholar]
  135. 135. 
    Zha H, Wang X, Zhu Y, Chen D, Han X et al. 2019. Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages. Cancer Immunol. Res. 7:193–207
    [Google Scholar]
  136. 136. 
    Cunha LD, Yang M, Carter R, Guy C, Harris L et al. 2018. LC3-associated phagocytosis in myeloid cells promotes tumor immune tolerance. Cell 175:429–41.e16
    [Google Scholar]
  137. 137. 
    Su S, Zhao J, Xing Y, Zhang X, Liu J et al. 2018. Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages. Cell 175:442–57.e23
    [Google Scholar]
  138. 138. 
    Wang W, Marinis JM, Beal AM, Savadkar S, Wu Y et al. 2018. RIP1 kinase drives macrophage-mediated adaptive immune tolerance in pancreatic cancer. Cancer Cell 34:757–74.e7
    [Google Scholar]
  139. 139. 
    Daley D, Mani VR, Mohan N, Akkad N, Ochi A et al. 2017. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 23:556–67
    [Google Scholar]
  140. 140. 
    Daley D, Mani VR, Mohan N, Akkad N, Pandian G et al. 2017. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J. Exp. Med. 214:1711–24
    [Google Scholar]
  141. 141. 
    Wei SC, Duffy CR, Allison JP 2018. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 8:1069–86
    [Google Scholar]
  142. 142. 
    Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G et al. 2010. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6Chigh monocytes. Cancer Res 70:5728–39
    [Google Scholar]
  143. 143. 
    Henze AT, Mazzone M. 2016. The impact of hypoxia on tumor-associated macrophages. J. Clin. Investig. 126:3672–79
    [Google Scholar]
  144. 144. 
    Jalkanen S, Aho R, Kallajoki M, Ekfors T, Nortamo P et al. 1989. Lymphocyte homing receptors and adhesion molecules in intravascular malignant lymphomatosis. Int. J. Cancer 44:777–82
    [Google Scholar]
  145. 145. 
    Lavin Y, Kobayashi S, Leader A, Amir ED, Elefant N et al. 2017. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169:750–65.e17
    [Google Scholar]
  146. 146. 
    Gubin MM, Esaulova E, Ward JP, Malkova ON, Runci D et al. 2018. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell 175:1014–30.e19
    [Google Scholar]
  147. 147. 
    Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D et al. 2018. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24:1277–89
    [Google Scholar]
  148. 148. 
    Mantovani A, Longo DL. 2018. Macrophage checkpoint blockade in cancer—back to the future. N. Engl. J. Med. 379:1777–79
    [Google Scholar]
  149. 149. 
    Lin H, Wei S, Hurt EM, Green MD, Zhao L et al. 2018. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression. J. Clin. Investig. 128:805–15
    [Google Scholar]
  150. 150. 
    Guerriero JL, Sotayo A, Ponichtera HE, Castrillon JA, Pourzia AL et al. 2017. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543:428–32
    [Google Scholar]
  151. 151. 
    Yang X, Feng W, Wang R, Yang F, Wang L et al. 2018. Repolarizing heterogeneous leukemia-associated macrophages with more M1 characteristics eliminates their pro-leukemic effects. OncoImmunology 7:e1412910
    [Google Scholar]
  152. 152. 
    Edwards DK 5th, Watanabe-Smith K, Rofelty A, Damnernsawad A, Laderas T et al. 2019. CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells. Blood 133:588–99
    [Google Scholar]
  153. 153. 
    Liu M, O'Connor RS, Trefely S, Graham K, Snyder NW, Beatty GL 2019. Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated ‘don't-eat-me’ signal. Nat. Immunol. 20:265–75
    [Google Scholar]
  154. 154. 
    Bianchini G, Gianni L. 2014. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol 15:e58–68
    [Google Scholar]
  155. 155. 
    McCracken MN, Cha AC, Weissman IL 2015. Molecular pathways: activating T cells after cancer cell phagocytosis from blockade of CD47 “don't eat me” signals. Clin. Cancer Res. 21:3597–601
    [Google Scholar]
  156. 156. 
    Massara M, Bonavita O, Savino B, Caronni N, Mollica Poeta V et al. 2018. ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity. Nat. Commun. 9:676
    [Google Scholar]
  157. 157. 
    Viitala MK, Virtakoivu R, Tadayon S, Rannikko J, Jalkanen S, Hollmen M 2019. Immunotherapeutic blockade of macrophage Clever-1 reactivates the CD8+ T-cell response against immunosuppressive tumors. Clin. Cancer Res. 25:3289–303
    [Google Scholar]
  158. 158. 
    Mantovani A, Bonecchi R. 2019. One clever macrophage checkpoint. Clin. Cancer Res 25:3202–4
    [Google Scholar]
  159. 159. 
    Lo Russo G, Moro M, Sommariva M, Cancila V, Boeri M et al. 2019. Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin. Cancer Res. 25:989–99
    [Google Scholar]
  160. 160. 
    Casey SC, Tong L, Li Y, Do R, Walz S et al. 2016. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352:227–31
    [Google Scholar]
  161. 161. 
    Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL et al. 2018. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin's lymphoma. N. Engl. J. Med. 379:1711–21
    [Google Scholar]
  162. 162. 
    Molgora M, Bonavita E, Ponzetta A, Riva F, Barbagallo M et al. 2017. IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551:110–14
    [Google Scholar]
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